These rare variants often act aggressively and may respond differently to therapy than the more common prostate adenocarcinoma.

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1 Prostate Cancer OVERVIEW Prostate cancer is the second most common cancer diagnosed among American men, accounting for nearly 200,000 new cancer cases in the United States each year. Greater than 65% of all cases of prostate cancer are diagnosed in men 65 years and older. The incidence of prostate cancer increases with age with the lifetime risk for the average American man is about one-in-six. Well-established risk factors include older age, family history, and race (African Americans are at greater risk). Other potential risk factors thought to be associated prostate cancer include a Western diet high in saturated fat and obesity. The overwhelming majority of prostate cancers are adenocarcinomas, which arises from the glandular component of the prostate. Other rare forms of prostate cancer include: Ductal carcinoma Mucinous carcinoma Signet-ring cell carcinoma Small cell carcinoma Clear cell adenocarcinoma Giant cell carcinoma These rare variants often act aggressively and may respond differently to therapy than the more common prostate adenocarcinoma. The face of prostate cancer has changed significantly over the past 2 decades. Largely due to the widespread use of serum prostate specific antigen (PSA) assay. Most prostate cancers are now diagnosed at an earlier stage and younger age compared to 20 years ago because of PSA assay. Although prostate cancer deaths have decreased in recent years, PSA screening continues to be controversial. However both the American Cancer Society and American Urologic Association recommend prostate cancer screening beginning at age 50 for most men and at 40 years of age for African American men and those with a family history. Localize prostate cancer Approximately 90% of prostate cancers are diagnosed at a localized stage (cancer confined to prostate without evidence of spread). Localized cancers are most commonly detected through an elevation in PSA without causing symptoms. Less commonly, prostate cancer may be detected by an abnormal digital rectal exam (DRE). Not all local prostate cancers are the same. Some are indolent and will not cause problems while others are clinically significant and require treatment. Even among clinically significant cancers, there are differences that further separate cancers by risk (for example, low, intermediate and high risk prostate cancer). Factors that determine the risk and thus clinical significance of prostate cancers include serum

2 PSA, Gleason score and clinical stage. There are several effective treatment options for men with localize prostate cancer, including surgery, external beam radiation therapy and interstitial brachytherapy. Treatment recommendations are usually made based on a number of factors, including overall health, disease characteristics, risk category, candidacy for a particular treatment, and patient preference. In some cases (low- and intermediate-risk prostate cancer, for example), a single treatment may be adequate for disease control. For others, particularly in high-risk prostate cancer, a combination of treatments may be required. For low-risk prostate cancer and among older men, active-surveillance (observation) is another management option. All prostate cancer treatments carry some risk of impacting urinary, sexual and bowel function. Newer treatment methods, however, continue to be developed to minimize the risks of these side effects (for example, nerve-sparing radical prostatectomy and image guided radiation therapy). Following treatment, approximately 15% to 25% of patients with early-stage (localized) prostate cancer experience a biochemical (PSA) recurrence (that is treatment failure). These individuals may require additional therapy. However, the overall 5-year survival for patients with localized prostate cancer is nearly 100%. Advanced prostate cancer Approximately 10% of prostate cancers are diagnosed at an advanced stage characterized by involvement of surrounding structures, spread to lymph nodes or spread to more distant sites (metastatic disease). Advanced prostate cancer more commonly causes some symptoms, such as hematuria, urinary obstruction or bone pain. Treatment options for patients with advanced prostate cancer are more limited, although in some settings, surgery or radiation therapy may still be indicated. More commonly, androgen deprivation therapy (ADT), also known as hormone therapy, is used to control the disease and slow the growth of these cancers. Chemotherapy may also be used to manage patients with metastatic prostate cancer. Common sites of metastatic spread include the bone, liver and lungs. The overall 5-year survival for regionally advanced and metastatic prostate cancer is approximately 32%. Signs & Symptoms For most men, prostate cancer does not cause symptoms but is detected because of an elevation in serum prostate specific antigen (PSA). However, symptoms of the lower urinary tract, such as hematuria (blood in the urine), frequency (need to urinate frequently) and dysuria (discomfort or pain with urination) may be signs of prostate problems, including prostate cancer. Other uncommon symptoms of prostate cancer can include urinary retention, weight loss, abdominal pain, bone pain, or fracture. Lower Urinary Tract Symptoms Frequency Urgency Hematuria (visible or microscopic) Dysuria Urinary retention

3 Pain Symptoms Back pain Pelvic pain Bone pain Constitutional symptoms Weight loss Diagnosis Physical examination Serum PSA test Prostate biopsy Abdominal and pelvic CT scan (if indicated) Bone scan (if indicated) After taking a detailed medical history and performing a physical examination, including a digital rectal examination, a PSA blood test will be performed. If the PSA level is elevated, a prostate biopsy may be recommended. The biopsy is an outpatient procedure that is performed with local anesthesia. Several samples of tissue are obtained from the prostate. These samples are sent to pathology, where the samples are reviewed under a microscope to detect cancerous cells. If the biopsy is positive, other tests may be performed based on your PSA level, cancer grade and findings on exam. In high-risk cases, a bone scan and/or CT scan of the pelvis may be recommended to determine if there has been spread to the bones or local organs. Staging for prostate cancer Clinical staging is performed with Physical Examination and Pelvic CT scan. In cases of advanced or high-risk disease, additional testing such as Bone Scan may be necessary. The prognosis of prostate cancer is directly linked to the grade and stage of disease. Staging is a process that demonstrates how far the cancer has spread. Both treatment options and prognosis (or outlook) for prostate cancer depend significantly on the stage of disease. TNM SYSTEM Status T0 No evidence of primary kidney tumor Clinically inapparent tumor not palpable or visable by T1 imaging Tumor incidental histologic finding in <5% of removed T1a tissue Tumor incidental histologic finding in >5% of removed T1b tissue

4 Tumor identified by needle biopsy because of elevated T1c PSA T2 Tumor confined with the prostate T2a Tumor involves one-half of one lobe or less T2b Tumor involves > one-half of one lobe but not both lobes T2c Tumor involves both lobes T3 Tumor extends through the prostate capsule T3a Extracapsular extension (unilateral or bilateral) T3b Tumor invades seminal vesicle(s) T4 Tumor fixed or invades adjacent pelvic structures N0 No regional lymph node metastasis N1 Metastasis in regional lymph node or nodes M0 No distant metastasis M1 Distant metastasis M1a Metastasis to non-regional lymph node(s) M1b Metastasis to bone(s) M1c Metastasis to other site(s) Treatment Most prostate cancers are localized and can be treated with surgery, external radiation therapy or interstitial brachytherapy. In low-risk disease, observation or active surveillance may also be an option. Focal therapy using ablative technology is less common and is currently under investigation. Treatments for localized prostate cancer include: Radical retropubic prostatectomy Robotic-assisted laparoscopic prostatectomy Intensity-modulated radiation therapy Interstitial brachytherapy Focal therapy Active Surveillance (observation) Radical retropubic prostatectomy (RRP) consists of removal of the prostate gland and surrounding lymph nodes through an 8 cm open incision above the pubic bone. Radical retropubic prostatectomy is the most common open surgical approach to treating prostate cancer, and can be used to treat a range of prostate cancer, including low, intermediate and high-risk localized prostate cancer, as well as radiation refractory prostate cancer (termed salvage prostatectomy). Patients spend 2 nights in the hospital and are sent home with a urinary (Foley) catheter, which stays in for a week following surgery to assist healing of the urethra. Depending on the stage and risk of the disease, radical retropubic prostatectomy can be performed with nerve-sparing. Nerve-sparing prostatectomy provides the best chance of return of erections following surgery in men with good erectile function prior to treatment, and is typically used in low and intermediate-risk disease. In setting of high-risk disease, however, nerve-

5 sparing may not be indicated as it may adversely affect cancer control. Like other types of surgical therapy, outcomes following radical retropubic prostatectomy (cancer control, urinary continence, erectile function and complications) tend to be better, on average, when performed by high-volume and fellowship-trained surgeons. Robotic-assisted laparoscopic prostatectomy (RALP) is one of the most common types of surgical treatments for prostate cancer and its use has increased rapidly over the recent years. Similar to radical retropubic prostatectomy, robotic-assisted laparoscopic prostatectomy is used in the management of localized prostate cancer. The robotic approach takes advantage of the benefits of laparoscopy as well as small surgical working elements that replicate the movement of the human hand. In general, RALP is associated with less blood loss, decreased pain post-operatively, and shorter convalescence. As with RRP, lymph nodes are removed with the prostate for pathologic staging. Patients tend to spend 1-2 nights in the hospital and are sent home with a urinary (Foley) catheter that stays in place for 7 to 10 days. As with open surgery, this procedure should be performed by a surgeon familiar with the robot and who is trained in performing radical prostatectomy. Intensity-Modulated Radiation Therapy Radiation therapy is an effective treatment for prostate cancer and can be used to manage low and high-risk cases. Current state of the art includes Intensity-modulated RT (IMRT), which uses more advanced technology to reduce dose to the areas of the bladder, rectum and bowel and boost dose to the prostate. In addition, the newer technology allows image guiding to more accurately deliver radiation dose to the prostate with less radiation therapy exposure to surrounding tissues. A total radiation dose of >76 Gy should be administered and some studies have shown that higher doses are more effective. Radiation therapy is typically given in daily fractions over the course of 10 weeks. Helical tomotherapy is currently the most advanced method of delivering IMRT to patients. This method uses a constantly modulated rotating beam of radiation that targets the exact size and shape of the tumor. This treatment is completely integrated so physicians know exactly what took place and where in the patient's previous treatment session. In intermediate- and high-risk prostate cancer, radiation should be administered with ADT to maximize the treatment effect. Interstitial prostate brachytherapy involves placement of small radioactive pellets, or seeds into the prostate. In general, this treatment can be used for small to normal sized prostates and for Gleason grade 6 or less tumors. In settings of higher risk disease (PSA>10 ng/ml or Gleason grade >7) where there is concern for extraprostatic extension, external radiation therapy should be used to ensure adequate cancer control. In some cases, hormone therapy may be used before brachytherapy to help reduce the size of the prostate. Active surveillance (observation) is used in some cases of low-risk disease, as well as among older patients for whom active treatment with surgery or radiation therapy may not be possible or necessary. Active surveillance is most often used because some prostate cancers may never become life threatening. PSA and DRE are typically

6 checked routinely, in addition repeat prostate biopsies are usually necessary to ensure the cancer is not progressing. Focal therapy ablative therapies such as cryoablation are currently being studied as a way to limit treatment to the focal location of the cancer instead of treating the entire prostate with the hopes that focal therapy will be associated with fewer side effects than other non-focal treatments. Selection of appropriate, low-risk patients is critical because less therapy may not be adequate to control higher-volume or high-risk prostate cancer. Salvage therapy In cases of prostate cancer recurrence following primary treatment, a secondary local therapy can lead to cure (salvage therapy). Depending on which type of treatment was first used, salvage surgery, radiation therapy or cyroabalation may be used to control recurrent disease. Treatment for advance prostate cancer Hormone therapy uses medications to decrease testosterone, a hormone that promotes growth of prostate cancer. This therapy may be done in cases of advanced prostate cancer. Hormones may also be given in conjunction with radiation therapy or surgery. Watchful waiting is another option that may be recommended, as prostate cancer generally grows slowly. Talk with your doctor about selecting your treatment and balancing the expected benefits. Chemotherapy is anticancer medications that are injected into a vein or given by mouth.